Endocrine/Metabolic Disorders Pharmacotherapy

1. II. Thyroid Disorders
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Chapter Four
Endocrine/Metabolic Disorders
Pharmacotherapy

2. Learning Objectives
• Explain the major components of the
hypothalamic–pituitary–thyroid axis and the
interaction among these components
• Discuss the relationship between serum TSH
levels and primary thyroid disease
• Identify the typical sns and sxs of hypo- and
hyper-thyroidism
• Describe the management of hypo- and hyper-
thyroidism
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3. Introduction
• Thyroid disorders encompass a variety of
disease states affecting
– thyroid hormone production or secretion that result in
alterations in metabolic stability.
• Hyperthyroidism and hypothyroidism are the
clinical and biochemical syndromes resulting
from
– increased and decreased thyroid hormone
production, respectively
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4. Thyroid Hormone Physiology
• Thyroid gland
– largest endocrine gland in the body
– residing in the neck anterior to the trachea b/n the
cricoid cartilage and the suprasternal notch.
– produces two biologically active hormones,
• thyroxine (T4) and triiodothyronine (T3)
• Thyroid hormones
– Essential for proper fetal growth & development,
particularly of the CNS
– After delivery, regulation of energy metabolism
– affect the function of virtually every organ in the body
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6. Thyroid Hormone Physiology
• T4 and T3 are transported in the bloodstream by
three proteins:
–thyroid-binding globulin, thyroid-binding pre-
albumin, and albumin
• Only the unbound (free) thyroid hormone is able to
diffuse into the cell, elicit a biologic effect, and
regulate TSH secretion from the pituitary
• T4 is secreted solely from the thyroid gland, but less
than 20% of T3 is produced there;
• Majority of T3 is formed from the breakdown of T4
catalyzed by the enzyme 5'-monodeiodinase found
in peripheral tissues. T3 is 5x more active than T4
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7. Thyroid Hormone Physiology
• Thyroid hormone production is regulated by:
–TSH secreted by the anterior pituitary, which in
turn is under:
• negative feedback control by the circulating level of
free thyroid hormone and
• positive influence of hypothalamic thyrotropin-
releasing hormone.
–Extrathyroidal deiodination of T4 to T3, which can
be affected by nutrition, non-thyroidal hormones,
drugs, and illness.
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8. Hypothalamic–pituitary–thyroid axis
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9. Blood Tests
• Thyroid Function Test
– measure serum TSH, free T4 & free T3
• Thyroid Autoantibody estimation .
– Antithyroid Ab
– Thyroglobulin Ab (TGAb)
– Ab against thyroid TSH receptors (TRAbs)
• Serum thyrogloublin
– Used in follow up of metastatic thyroid carcinoma after
thyroidectomy
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10. TSH
Low
High
FT4 FT4 & FT3
Low
1° Hypothyroid
Low
Central
Hypothyroid
High
1° Thyrotoxicosis
High
2° thyrotoxicosis

11. Thyrotoxicosis (Hyperthyroidism)
• Hyperthyroidism is related to excess thyroid
hormone secreted by the thyroid gland.
• Thyrotoxicosis is any syndrome caused by
excess thyroid hormone and can be related to
excess hormone production (hyperthyroidism)
• Graves’ disease is the most common cause of
hyperthyroidism
• Thyrotoxicosis in the elderly is more likely
caused by toxic thyroid nodules or multinodular
goiter than by Graves’ disease
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13. Causes of Thyrotoxicosis....
• In Graves’ disease, hyperthyroidism results from :
– the action of thyroid-stimulating antibodies (TSAb)
directed against the thyrotropin receptor on the surface
of the thyroid cell.
• In multinodular goiters (Plummer’s disease):
– Thyrotoxicosis occurs when the autonomous follicles
generate more thyroid hormone than is required
• Painful sub-acute (granulomatous or de
Quervain’s) thyroiditis is believed to be caused by
– viral invasion of thyroid parenchyma
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14. Thyrotoxicosis (Hyperthyroidism)
• Thyrotoxicosis factitia is hyperthyroidism
produced by the ingestion of exogenous thyroid
hormone
• Amiodarone may induce thyrotoxicosis (2% to
3% of patients) or hypothyroidism
– It interferes with type I 5'-deiodinase, leading to
reduced conversion of T4 to T3, and iodide release
from the drug may contribute to iodine excess.
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17. Thyroid storm
• Thyroid storm is a life-threatening medical
emergency characterized by:
– severe thyrotoxicosis,
– high fever (often greater than 39.4°C [103°F]),
– tachycardia, tachypnea, dehydration, delirium, coma,
nausea, vomiting, and diarrhea.
• Precipitating factors include:
– infection, trauma, surgery, radioactive iodine (RAI)
treatment, and withdrawal from antithyroid drugs.
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18. Treatment: Desired Outcome
• Therapeutic objectives for hyperthyroidism
are :
– To normalize the production of thyroid
hormone
– To minimize symptoms and long-term
consequences
– To provide individualized therapy based on the
type and severity of disease, patient age and
gender, existence of nonthyroidal conditions,
and response to previous therapy.
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19. Nonpharmacologic Therapy
• Surgical removal of the thyroid gland should be
considered in patients with:
– a large gland (>80 g)
– severe ophthalmopathy, or
– a lack of remission on antithyroid drug treatment
• If thyroidectomy is planned,
– Propylthiouracil(PTU) or methimazole(MMI) is usually
given until the pt is biochemically euthyroid (usually 6
to 8 weeks)
– followed by the addition of iodides (500 mg/day) for 10
to 14 days before surgery to decrease the vascularity
of the gland
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20. Nonpharmacologic Therapy
• If thyroidectomy is planned…
– Levothyroxine may be added to maintain the
euthyroid state while the thionamides are continued
– Propranolol has been used for several weeks
preoperatively and 7 to 10 days after surgery to
maintain a pulse rate less than 90 beats/min.
– Combined pretreatment with propranolol and 10 to 14
days of potassium iodide also has been advocated.
• Complications of surgery
– Persistent or recurrent hyperthyroidism (0.6% to
18%), hypothyroidism (up to about 49%),
hypoparathyroidism (up to 4%), and vocal cord
abnormalities (up to 5%)
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21. Pharmacologic Therapy
• Thioureas (Thionamides)
• Iodides
• Adrenergic Blockers
• Radioactive Iodine
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22. Thioureas (Thionamides)
• PTU & MMI block thyroid hormone synthesis by
– inhibiting the peroxidase enzyme system
– preventing oxidation/organification
– inhibiting coupling of MIT & DIT to form T4 & T3
– PTU (but not MMI) also inhibits the peripheral
conversion of T4 to T3
• Usual initial doses
– PTU 300 to 600 mg daily (usually in three or four
divided doses) or
– MMI 30 to 60 mg daily given in three divided doses.
• Evidence exists that both drugs can be given as a single
daily dose.
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23. Thioureas (Thionamides)
• Improvement in symptoms and laboratory
abnormalities should occur within 4 to 8 weeks,
at which time a tapering regimen to maintenance
doses can be started
• Dosage changes should be made on a monthly
basis because the endogenously produced T4
will reach a new steady-state concentration in
this interval
• Typical daily maintenance doses are PTU 50 to
300 mg and MMI 5 to 30 mg
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24. Thioureas (Thionamides)
• Therapy should continue for 12 to 24 months
to induce a long-term remission.
• Patients should be monitored every 6 to 12
months after remission
• If a relapse occurs, alternate therapy with
RAI is preferred to a second course of
antithyroid drugs, as subsequent courses of
therapy are less likely to induce remission
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25. Thioureas (Thionamides)
• Major adverse effects include:
– agranulocytosis (with fever, malaise, gingivitis,
oropharyngeal infection, and a granulocyte count
less than 250/mm3),
– aplastic anemia,
– a lupus-like syndrome,
– polymyositis, GI intolerance,
– hepatotoxicity, and
– hypoprothrombinemia.
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26. Iodides
• Iodide acutely:
– blocks thyroid hormone release,
– inhibits thyroid hormone biosynthesis by interfering
with intrathyroidal iodide use, and
– decreases the size and vascularity of the gland.
• Symptom improvement occurs within 2 to 7 days
of initiating therapy, and serum T4 and T3
concentrations may be reduced for a few weeks
• Iodides are often used as adjunctive therapy to:
– prepare a pt with Graves’ disease for surgery
– to inhibit thyroid hormone release after RAI therapy.
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27. Iodides
• Iodides are often used as adjunctive therapy…
– to acutely inhibit thyroid hormone release and quickly
attain the euthyroid state in severely thyrotoxic
patients with cardiac decompensation, or
• Potassium iodide is available as a
– Saturated solution KI (SSKI, 38 mg iodide per drop)
– Lugol’s solution, containing 6.3 mg of iodide per drop
• The typical starting dose of SSKI is 3 to 10 drops
daily (120 to 400 mg) in water or juice
• As an adjunct to RAI, SSKI should not be used
before but rather 3 to 7 days after RAI treatment
so that the RAI can concentrate in the thyroid.
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28. Iodides
• Adverse effects include;
– hypersensitivity reactions (skin rashes, drug fever,
rhinitis, conjunctivitis)
– salivary gland swelling
– “iodism” (metallic taste, burning mouth and throat,
sore teeth and gums and sometimes stomach upset
and diarrhea)
– gynecomastia
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29. Adrenergic Blockers/ β-Blockers
• Used widely to ameliorate thyrotoxic sxs such as
palpitations, anxiety, tremor, and heat intolerance
• Propranolol and nadolol partially block the
conversion of T4 to T3, but this contribution to
the overall therapeutic effect is small.
• Usually used as adjunctive therapy with
antithyroid drugs, RAI, or iodides
• Are primary therapy only for thyroiditis and
iodine-induced hyperthyroidism
• Propranolol initial dose of 20 to 40 mg four times
daily is effective for most pts (HR ˂90 beats/min)
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30. Adrenergic Blockers/ β-Blockers
• Younger or more severely toxic patients may
require as much as 240 to 480 mg/day
• Contraindicated in patients with:
– Decompensated HF unless it is caused solely by
tachycardia (high output)
– Sinus bradycardia, concomitant therapy with MAO-
inhibitors or TCAs, and spontaneous hypoglycemia
• Centrally acting sympatholytics (e.g., clonidine)
and CCBs(e.g., diltiazem)
– useful for symptom control when contraindications to
β-blockade exist
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31. Radioactive Iodine
• Agent of choice for Graves’ disease, toxic
autonomous nodules, and toxic multinodular
goiters
• Pregnancy is an absolute contraindication to the
use of RAI
• Pts with cardiac disease and elderly pts are often
treated with thionamides prior to RAI ablation
because thyroid hormone levels will transiently
increase after RAI treatment due to release of
preformed thyroid hormone
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32. Treatment of Thyroid Storm
• The following therapeutic measures should
be instituted promptly:
1. Suppression of thyroid hormone formation
and secretion
2. Antiadrenergic therapy
3. Administration of corticosteroids; and
4. Treatment of associated complications or
coexisting factors that may have precipitated
the storm
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33. Treatment of Thyroid Storm
• PTU in large doses is the preferred thionamide
• Iodides, which rapidly block the release of
preformed thyroid hormone, should be
administered after PTU is initiated to inhibit
iodide use by the overactive gland.
• Antiadrenergic therapy with the short-acting
agent esmolol is preferred
• Corticosteroids are generally recommended
– their benefits may be attributed to their antipyretic
action and stabilization of blood pressure.
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34. Treatment of Thyroid Storm
• General supportive measures
– Acetaminophen as an antipyretic (aspirin or other
NSAIDs may displace bound thyroid hormone),
– Fluid and electrolyte replacement
– Sedatives, digoxin, antiarrhythmics, insulin, and
antibiotics should be given as indicated
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35. Evaluation Of Therapeutic Outcomes
• After therapy (thionamides, RAI, or surgery) for
hyperthyroidism has been initiated, patients
should be evaluated on a monthly basis until
they reach a euthyroid condition.
• Clinical signs of continuing thyrotoxicosis or the
development of hypothyroidism should be noted.
• maintain both the free T4 level and the TSH
concentration in the normal range.
• Once a stable dose of T4 is identified, the patient
may be followed every 6 to 12 months.
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36. Hypothyroidism
• Most common clinical disorder of thyroid function
• Deficiency in circulating levels of thyroid
hormone leads to hypothyroidism and, in
neonates, to cretinism, which is characterized by
neurologic impairment and mental retardation
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40. Treatment
• T4 is the treatment of choice
• Administered in dosages varying from 50 to 200
microgram per day, depending upon the patient's
size and condition.
• Starting doses of 100 µg of T4 daily are well
tolerated
• Lower dose such as 25 to 50 µg daily
– Elderly pts and those with coexisting heart disease
and profound hypothyroidism b/c of associated
hypercholesterolemia and atherosclerosis.
• The dose can be slowly increased over weeks to
months to attain a euthyroid state.
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41. Treatment
• A baseline ECG should always be obtained in
patients with severe hypothyroidism before
treatment
• T4 dosage is titrated against clinical response
and TSH levels, which should return to normal.
• Patients who present with myxedema coma may
require initial emergency treatment with large
doses of IV T4 (300 to 400 µg), with careful
monitoring in an intensive care unit setting.
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43. Myxedema Coma
• Extremely rare condition, is the end stage of
untreated hypothyroidism.
• Progressive weakness, stupor, hypothermia,
hypoventilation, hypoglycemia, & hyponatremia,
and it may ultimately result in shock and death
• Mortality rate > 50%
• Treatment of Myxedema Coma
– Admit to ICU for ventilatory support and for
intravenous medications
– Parenteral thyroxine
• LD of 300–400 μg IV, then 50 μg IV daily. (May also give
liothyronine sodium, 10 μg IV every 8 hours for the first 48
hours if necessary.) 43

44. Myxedema Coma
• Treatment of Myxedema Coma….
– Electrolytes: Water restriction for hyponatremia. Avoid
fluid overload.
– Limit sedation. Appropriate reduction in drug dosage.
– Glucocorticoids: Controversial but necessary in
hypopituitarism or polyglandular failure.
• Dosage: Hydrocortisone sodium phosphate or sodium
succinate, 40–100 mg every 6 hours initially and taper
downward over 1 week. (If initial serum cortisol was > 30
μg/dL, corticosteroids are unnecessary).
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